We have demonstrated that the HIV-1 accessory protein Vpr acts as a potent coactivator of the glucocorticoid receptor (GR), increasing the sensitivity of transfected cells to glucocorticoids by many fold. It accomplishes this by binding to the GR through a coactivator motif LXXLL, by interacting with amino acid 2141-2195 of the cointegrrator p300 -which contains a binding site of p160 nuclear receptor coactivators- functioning as a potentiator of the nuclear receptor coactivator system and several elements of the RNA polymerase II into a ternary transcription/elongation complex. We have demonstrated that the HIV-1 protein Tat stimulates the HIV-1 LTR by participating in a similar ternary complex containing p160 nuclear receptor coactivatorsand Vpr. Indeed, Tat, and its partner protein CyclinT1, bind to N-terminus of p160 coactivators and enhance accumulation of elongation complex p-TEFb to the coactivator complex. Vpr functions as an enhancer of Tat-stimulated HIV-1-LTR and nuclear receptor-governed promoters, functioning as a potentiator of nuclear receptor coactivator system. By modulation of coactivator activites, Vpr may enhance viral replication/proliferation both directly and indirectly. Using a yeast two-hybrid screening, we found that Vpr strongly associates with the 14-3-3 protein, through which Vpr arrests host cell cycle at G2/M phase. Based on the above in vitro evidence, we will proceed to examine the in vivo actions of Vpr in transgenic mice which conditionally express wild type Vpr or two of its mutants that have respectively lost either their GR coactivator or the cell cycle arresting activity; and, (3) the in vivo expression and effects of Vpr in HIV-1-infected humans. The GR coactivator activity of Vpr can explain the immunosuppression, muscular atrophy and lipodystrophic visceral adiposity of patients with AIDS.